Short Genes Have More Activity During Aging Than Long Genes

 A new sign of ageing is discovered by closely examining gene activity in many creatures, including humans.

By Diana Kwon on Jan 06, 2023

Genes that make up our DNA have a wide range of sizes. Genes in humans can range in length from a few hundred base molecules to two million bases. These genes include data necessary to maintain the body's functionality, including instructions for building proteins. According to a recent study, longer genes become less active as we age than shorter ones. And comprehending this phenomena could make it possible to find novel techniques to delay ageing.

Professor Lus Amaral of chemical and biological engineering at Northwestern University claims that the goal of his team's first research was not to measure gene length. As mice matured, some of Amaral's Northwestern coworkers had been attempting to identify changes in gene expression—the process by which the data in a piece of DNA is utilised to generate a functional product, such as a protein or bit of genetic material called RNA. But it was difficult for them to spot recurring changes. Amaral observes that "nearly everything looked to be random."

Then, on the advice of a postdoctoral researcher named Thomas Stoeger The group chose to take gene length changes into account at Amaral's lab. The amount of RNA declines with age, and disruptions to transcription—the process by which RNA copies, or transcripts, are formed from DNA templates—can have a greater impact on longer genes than shorter ones—had been shown in earlier studies to suggest that there may be such a large-scale change in gene activity with age.

In order to find characteristics that best described changes in RNA from 17 various tissues, including the heart, brain, and kidney, in male mice that were four, nine, twelve, eighteen, and twenty-four months old, Stoeger, Amaral, and his colleagues employed a machine-learning algorithm. (At 24 months, the strain of mice utilised in this study is regarded as "extremely elderly"). With age, longer transcripts became less prevalent than shorter transcripts, according to this analysis's findings across tissues. They may have been unable to identify a particular group of genes whose expression was changing, but this imbalance in long- and short-gene expression offered a potential explanation.

Overall, shorter genes tended to become more active than longer genes as animals aged, although the specific genes being expressed differed from experiment to experiment, according to Amaral. Hundreds of genes will constantly appear to change, but if you understand it in terms of this linear trend, everything makes sense, he claims. (Amaral points out that while transcriptional alterations are most likely to account for his and his team's findings, other mechanisms, such as RNA degradation, may also be at work.)

The scientists conducted this experiment again using information gathered from other postmortem human tissue types and tissues taken at particular ages from other animals. They discovered that this imbalance in gene-length-related expression that is connected to ageing is present in all species. According to Amaral, the human findings were especially intriguing since, in contrast to the mice, who were genetically similar and grown under the same laboratory settings, the humans had varied lifestyles and died of various illnesses at various periods. The fact that you can still uncover a pattern despite this variance indicates that this idea is strong, the author claims. "That outcome significantly boosts my confidence in the validity and significance of this pattern."

When Amaral and his colleagues compared the longest and shortest transcripts, they discovered that the top 5% of genes with the shortest transcripts included many that were associated with shorter life spans, such as those involved in immune function and preserving the length of telomeres (DNA sequences at the ends of chromosomes that get shorter with age). Additionally, they discovered that genes associated with longevity, such as those involved in neural activity and transcriptional control, were in the top 5% of genes with the longest transcripts.By reevaluating data from previously published animal research, they also looked at how 12 antiaging therapies affected the balance of short- and long-gene activity. Seven of these therapies, including the antiaging medications rapamycin and resveratrol, caused a relative rise in long-gene transcripts, indicating that this aging-related imbalance may be reversed. The results were released in Nature Aging in December.

Maria Ermolaeva, a group leader at the Leibniz Institute of Aging in Germany who was not involved in the study, believes that this research is consistent with other findings. For instance, studies have revealed that longer genes are more susceptible to the cumulative effects of DNA damage throughout ageing; the longer the gene, the higher the risk that it would have a problem that cannot be fixed. Such unrepaired DNA lesions impede transcription, which decreases the amount of transcripts generated from longer genes. According to Ermolaeva, "the authors of the present study may have detected the worldwide effects of this previously documented molecular phenomena."

Although the authors' observation of a transcriptome imbalance with ageing "is an interesting association," Joo Pedro de Magalhes, a professor of molecular biogerontology at the University of Birmingham in England who was also not involved in this study, says it is still unclear whether this process is what causes ageing. Although I wouldn't rule it out completely, he adds, "I think you will need some very compelling proof that we don't have now." It's possible that changes in the transcriptome associated with length are only a reflection of aging-related processes, including an increase in immune system activity. According to de Magalhes, small genes are frequently linked to immune function, and as we age, immunological processes like inflammation become more active. In light of the mechanisms that are changing with age, it makes some sense that trends in gene length would be seen.

Amaral hypothesises that the imbalance in transcription may be brought on by a lifetime accumulation of dangerous exposures—viral infections, for instance—that gradually change the cellular machinery necessary to effectively transcribe longer genes. Perhaps age is a measure of this imbalance; the older you are and the older your tissue is, the bigger the imbalance. Amaral plans to investigate how injuries affect the transcriptome imbalance in younger organisms in the future. She also hopes to determine whether antiaging therapies can help correct the imbalance that develops after potentially harmful exposures.

There are still many unanswered problems, according to Amaral, such as how exactly the transcriptional machinery changes with ageing. "We hope our study will inspire individuals to do trials that might help us better understand what's going on," the authors write.